V O L U M E
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`J U L Y 1
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`2 0 1 4
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`JOURNAL OF CLINICAL ONCOLOGY
`
`A S C O S P E C I A L A R T I C L E
`
`Sharon H. Giordano and Ana M.
`Gonzalez-Angulo, University of Texas
`MD Anderson Cancer Center, Houston;
`Debra A. Patt, Texas Oncology, Austin,
`TX; Sarah Temin, American Society of
`Clinical Oncology, Alexandria, VA;
`Jeffrey J. Kirshner, Hematology/Oncol-
`ogy Associates of Central New York,
`East Syracuse; Sarat Chandarlapaty and
`Shanu Modi, Memorial Sloan Kettering
`Cancer Center; Francisco J. Esteva,
`New York University Cancer Institute,
`New York, NY; Jennie R. Crews,
`PeaceHealth St Joseph Cancer Center,
`Bellingham, WA; Nancy E. Davidson,
`University of Pittsburgh Cancer Institute
`and University of Pittsburgh Medical
`Center Cancer Center, Pittsburgh, PA;
`Ian Krop, Nancy U. Lin, and Eric P.
`Winer, Dana-Farber Cancer Institute,
`Boston, MA; Jennifer Levinson, Ponte
`Vedra Beach; Edith A. Perez, Mayo
`Clinic, Jacksonville; Naren Ramakrishna,
`University of Florida Health Cancer
`Center at Orlando Health, Orlando, FL;
`and Jane Perlmutter, Ann Arbor, MI.
`
`Published online ahead of print at
`www.jco.org on May 5, 2014.
`
`Clinical Practice Guideline Committee
`approval: November 19, 2013.
`
`Editor’s note: This American Society of
`Clinical Oncology Clinical Practice
`Guideline provides recommendations,
`with review and analyses of the rele-
`vant literature for each recommenda-
`tion. Additional information, including a
`Data Supplement with additional
`evidence tables, a Methodology Supple-
`ment, slide sets, clinical tools and
`resources, and links to patient informa-
`tion, is available at www.asco.org/
`guidelines/treatHER2pos, and a
`companion guideline is available at
`www.asco.org/guidelines/
`her2brainmets.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: American Soci-
`ety of Clinical Oncology, 2318 Mill Rd,
`Suite 800, Alexandria, VA 22314;
`e-mail: guidelines@asco.org.
`
`© 2014 by American Society of Clinical
`Oncology
`
`0732-183X/14/3219w-2078w/$20.00
`
`DOI: 10.1200/JCO.2013.54.0948
`
`Systemic Therapy for Patients With Advanced Human
`Epidermal Growth Factor Receptor 2–Positive Breast
`Cancer: American Society of Clinical Oncology Clinical
`Practice Guideline
`Sharon H. Giordano, Sarah Temin, Jeffrey J. Kirshner, Sarat Chandarlapaty, Jennie R. Crews,
`Nancy E. Davidson, Francisco J. Esteva, Ana M. Gonzalez-Angulo, Ian Krop, Jennifer Levinson, Nancy U. Lin,
`Shanu Modi, Debra A. Patt, Edith A. Perez, Jane Perlmutter, Naren Ramakrishna, and Eric P. Winer
`See accompanying article on page 2100
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`To provide evidence-based recommendations to practicing oncologists and others on systemic
`therapy for patients with human epidermal growth factor receptor 2 (HER2) –positive advanced
`breast cancer.
`Methods
`The American Society of Clinical Oncology convened a panel of medical oncology, radiation
`oncology, guideline implementation, and advocacy experts and conducted a systematic literature
`review from January 2009 to October 2012. Outcomes of interest included overall survival,
`progression-free survival (PFS), and adverse events.
`Results
`A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS
`benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial
`found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment.
`T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted
`therapy, and three others reported on endocrine therapy for patients with HER-positive advanced
`breast cancer.
`Recommendations
`HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer,
`except for those with clinical congestive heart failure or significantly compromised left ventricular
`ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and
`taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the
`third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if
`not previously administered) and may offer pertuzumab, if the patient has not previously received
`it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response,
`depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until
`time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen
`receptor–positive/progesterone receptor–positive breast cancer, clinicians may recommend either
`standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy
`or endocrine therapy alone.
`
`J Clin Oncol 32:2078-2099. © 2014 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Over the past decade, many new systemic therapies
`have become available for the treatment of advanced
`breast cancer. In particular, the treatment of hu-
`man epidermal growth factor receptor 2 (HER2)–
`positive breast cancer has evolved because of the
`development of HER2-targeted therapies that have
`
`been shown to improve survival for patients with
`early-stage or metastatic breast cancer. Approxi-
`mately 15% of patients with breast cancer have
`tumors that overexpress the HER2 protein, and
`these patients can benefit from HER2-targeted
`therapies.1,2 Brain metastases are common in
`patients with HER2-positive metastatic breast can-
`cer, with up to half of patients experiencing
`
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`© 2014 by American Society of Clinical Oncology
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`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`IMMUNOGEN 2224, pg. 1
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`HER2-Targeted Therapy Regimens for Patients With Advanced Breast Cancer
`
`THE BOTTOM LINE
`
`GUIDELINE QUESTION
`
`What is the optimal medical therapy for advanced human epidermal growth factor receptor 2
`(HER2) –positive breast cancer, specifically HER2-targeted therapy, either alone or in combination with
`chemotherapy and/or endocrine therapy?
`
`Target Population
`● Individuals with advanced HER2-positive breast cancer
`
`Target Audience
`● Medical oncologists, radiation oncologists, surgeons, oncology nurses, and patients/caregivers
`
`Recommendations
`● Clinicians should recommend HER2-targeted therapy– based combinations for first-line treatment, except for highly selected pa-
`tients with estrogen receptor (ER) –positive or progesterone receptor (PgR) –positive and HER2-positive disease, for whom clini-
`cians may use endocrine therapy alone. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians
`should recommend second-line HER2-targeted therapy– based treatment. Type: evidence based. Evidence quality: high. Strength
`of recommendation: strong.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treat-
`ment, clinicians should recommend third-line or greater HER2-targeted therapy– based treatment. Type: evidence based.
`Evidence quality: intermediate. Strength of recommendation: moderate.
`● Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the pa-
`tient has a contraindication to taxanes. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians
`should recommend trastuzumab emtansine (T-DM1) as second-line treatment. Type: evidence based. Evidence quality: high.
`Strength of recommendation: strong.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted therapy,
`but she has not received T-DM1, clinicians should offer T-DM1. Type: evidence based. Evidence quality: high. Strength of recom-
`mendation: strong.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treat-
`ment, but she has not received pertuzumab, clinicians may offer pertuzumab. Type: informal consensus. Evidence quality: insuffi-
`cient. Strength of recommendation: weak.
`● If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treat-
`ment, and she has already received pertuzumab and T-DM1, clinicians should recommend third-line or greater HER2-targeted
`therapy– based treatment. Options include lapatinib plus capecitabine, as well as other combinations of chemotherapy, and
`trastuzumab, lapatinib and trastuzumab, or hormonal therapy (in patients with ER-positive and/or PgR-positive disease). There
`is insufficient evidence to recommend one regimen over another. Type: informal consensus. Evidence quality: insufficient.
`Strength of recommendation: weak.
`● If a patient is receiving HER2-targeted therapy and chemotherapy combinations, the chemotherapy should continue for approxi-
`mately 4 to 6 months (or longer) and/or to the time of maximal response, depending on toxicity and in the absence of progres-
`sion. When chemotherapy is stopped, clinicians should continue the HER2-targeted therapy; no further change in the regimen is
`needed until the time of progression or unacceptable toxicities. Type: evidence based. Evidence quality: intermediate. Strength
`of recommendation: moderate.
`● If a patient finished trastuzumab-based adjuvant treatment ⱕ 12 months before recurrence, clinicians should follow the second-
`line HER2-targeted therapy– based treatment recommendations. Type: evidence based. Evidence quality: intermediate. Strength
`of recommendation: moderate.
`● If a patient finished trastuzumab-based adjuvant treatment ⬎ 12 months before recurrence, clinicians should follow the first-line
`HER2-targeted therapy– based treatment recommendations. Type: evidence based. Evidence quality: high. Strength of
`recommendation: strong.
`● If a patient’s cancer is hormone receptor positive and HER2 positive, clinicians may recommend either:
`• HER2-targeted therapy plus chemotherapy. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
`(continued on following page)
`
`www.jco.org
`
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
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`Giordano et al
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`THE BOTTOM LINE (CONTINUED)
`
`• Endocrine therapy plus trastuzumab or lapatinib (in selected cases). Type: evidence based. Evidence quality: high. Strength
`of recommendation: moderate.
`• Endocrine therapy alone (in selected cases). Type: evidence based. Evidence quality: intermediate. Strength of
`recommendation: weak.
`● If a patient has started with an HER2-positive targeted therapy and chemotherapy combination, clinicians may add endocrine
`therapy to the HER2-targeted therapy when chemotherapy ends and/or when the cancer progresses. Type: informal consensus.
`Evidence quality: insufficient. Strength of recommendation: weak.
`● In special circumstances, such as low disease burden, presence of comorbidities (contradictions to HER2-targeted therapy such as
`congestive heart failure), and/or presence of a long disease-free interval, clinicians may offer first-line endocrine therapy alone.
`Type: informal consensus. Evidence quality: intermediate. Strength of recommendation: weak.
`● Qualifying statement: Although clinicians may discuss using endocrine therapy with or without HER2-targeted therapy, the ma-
`jority of patients will still receive chemotherapy plus HER2-targeted therapy.
`● Note: The guide for rating recommendations and evidence quality is provided in the Methodology Supplement.
`
`Additional Resources
`
`Additional information, including a Data Supplement, a Methodology Supplement, evidence tables, and clinical tools and resources, can
`be found at www.asco.org/guidelines/treatHER2pos. Patient information is available there and at www.cancer.net.
`
`brain metastases. Recommendations for the management of brain
`metastases in patients with HER2-positive breast cancer are detailed in
`a companion guideline.3
`The rationale for this guideline is that several new agents have
`been approved by the US Food and Drug Administration (FDA) for
`the treatment of metastatic HER2-positive breast cancer since the
`approval of trastuzumab. This guideline reviews the evidence and
`provides guidance for optimal management of patients with HER2-
`positive metastatic breast cancer. A limited portion of the evidence
`base of this guideline (specifically regarding evidence on trastuzumab
`published before 2009) was included from two systematic reviews
`from Cancer Care Ontario (CCO) and from the systematic review by
`the American Society of Clinical Oncology (ASCO). The ASCO review
`both updated the CCO search on trastuzumab and included a broader
`search on additional ASCO clinical questions. The Expert Panel used
`results from the CCO systematic reviews in formulating recommen-
`dations discussed in Questions 1.A.I and 1.B.IV.4,5 The ASCO recom-
`mendations were developed by ASCO and are not based on the
`CCO recommendations.
`This guideline includes recommendations concerning the use of
`trastuzumab and newer agents in first- and second-line treatment,
`including combination therapies. Approximately half of all HER2-
`positive breast cancers are also hormone receptor positive. The depen-
`dency of HER2-positive, hormone receptor–positive tumors on
`estrogen signaling is only partially understood. This guideline ad-
`dresses what is known about the use of endocrine therapy for patients
`who have tumors that are both HER2 positive and hormone receptor
`positive. This guideline will not discuss HER2 testing, other than
`noting that quality HER2 testing is required for appropriate identifi-
`cation and management of HER2-positive patients. ASCO–College of
`American Pathologists recommendations for HER2 testing in breast
`cancer were recently published.6
`
`GUIDELINE QUESTIONS
`
`This clinical practice guideline addresses four overarching clinical
`questions: First, what are the optimal treatments for patients with
`HER2-positive advanced breast cancer in first-, second-, and third-
`line treatment and beyond? Second, what are the optimal timing, dose,
`schedule, and duration of treatment? Third, how should any previous
`HER2 adjuvant therapy influence treatment? And fourth, how does
`estrogen receptor (ER)/progesterone receptor (PgR) status influence
`decisions about treatment of patients with HER2-positive, hormone
`receptor–positive advanced breast cancer?
`
`METHODS
`
`Guideline Development Process
`The recommendations were developed by a multidisciplinary group of experts
`(Appendix Table A1, online only) using a systematic review of phase III
`randomized controlled trials (RCTs) and clinical experience as a guide. An
`ASCO systematic review in Medline was conducted. Most of the recommen-
`dations are evidence based and rely on publications found in literature
`searches from 2009 to October 2012 (trastuzumab) and from 1966 to 2012
`(nontrastuzumab agents). Literature on trastuzumab, specifically articles pub-
`lished before 2009, was included in an earlier CCO systematic review (Meth-
`odology Supplement). In some selected cases, where evidence was lacking, but
`there was a high level of agreement among panel members, informal consen-
`sus was used (as noted in Bottom Line box).
`Articles were selected for inclusion in the systematic review of evidence if
`they met the following criteria: fully published or recent meeting presentations
`of English-language reports of phase III RCTs or rigorously conducted system-
`atic reviews or meta-analyses; studies involving a population of patients with
`HER2-positive advanced breast cancer; and trials comparing a targeted agent
`(⫾ chemotherapy and ⫾ endocrine therapy) with another treatment regimen,
`placebo, or observation. Meeting abstracts were included only if the presenta-
`tion or poster was available.
`
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`JOURNAL OF CLINICAL ONCOLOGY
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`IMMUNOGEN 2224, pg. 3
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`HER2-Targeted Therapy Regimens for Patients With Advanced Breast Cancer
`
`Articles were excluded from the systematic review if they were: meeting
`abstracts not subsequently published in peer-reviewed journals; editorials,
`commentaries, letters, news articles, case reports, or narrative reviews; and
`published in a language other than English. The guideline recommendations
`were crafted, in part, using the Guidelines Into Decision Support (GLIDES)
`methodology and accompanying BRIDGE-Wiz software (http://gem
`.med.yale.edu/BRIDGE-Wiz). Ratings for type of recommendation and
`strength of evidence are provided in the Methodology and Data Supplements.
`Detailed information about the methods used to develop this guideline,
`regarding the Expert Panel composition, guideline development process, and
`steps taken in the systematic review and recommendation development pro-
`cess, is available in the Methodology and Data Supplements at www.asco.org/
`guidelines/treatHER2pos.
`Guideline Disclaimer
`The clinical practice guidelines and other guidance published herein are
`provided by ASCO to assist providers in clinical decision making. The infor-
`mation herein should not be relied on as being complete or accurate, nor
`should it be considered as inclusive of all proper treatments or methods of care
`or as a statement of the standard of care. With the rapid development of
`scientific knowledge, new evidence may emerge between the time information
`is developed and when it is published or read. The information is not contin-
`ually updated and may not reflect the most recent evidence. The information
`addresses only the topics specifically identified herein and is not applicable to
`other interventions, diseases, or stages of diseases. This information does not
`mandate any particular course of medical care. Furthermore, the information
`is not intended to substitute for the independent professional judgment of the
`treating provider, because the information does not account for individual
`variation among patients. Each recommendation reflects high, moderate, or
`low confidence that the recommendation reflects the net effect of a given
`course of action. The use of words like must, must not, should, and should not
`indicates that a course of action is recommended or not recommended for
`either most or many patients, but there is latitude for the treating physician to
`select other courses of action in individual cases. In all cases, the selected course
`of action should be considered by the treating provider in the context of
`treating the individual patient. Use of the information is voluntary. ASCO
`provides this information on an as-is basis and makes no warranty, express or
`implied, regarding the information. ASCO specifically disclaims any warran-
`ties of merchantability or fitness for a particular use or purpose. ASCO as-
`sumes no responsibility for any injury or damage to persons or property
`arising out of or related to any use of this information or for any errors
`or omissions.
`Guideline and Conflicts of Interest
`The Expert Panel was assembled in accordance with the ASCO Conflicts
`of Interest Management Procedures for Clinical Practice Guidelines (summa-
`rized at http://www.asco.org/rwc). Members of the panel completed the
`ASCO disclosure form, which requires disclosure of financial and other inter-
`ests that are relevant to the subject matter of the guideline, including relation-
`ships with commercial entities that are reasonably likely to experience direct
`regulatory or commercial impact as a result of promulgation of the guideline.
`Categories for disclosure include employment relationships, consulting ar-
`rangements, stock ownership, honoraria, research funding, and expert testi-
`mony. In accordance with these procedures, the majority of the members of
`the panel did not disclose any such relationships.
`Search Results
`A total of nine first-line, three second-line, and four beyond–second-line
`phase III randomized clinical trials were deemed eligible for inclusion in the
`ASCO systematic review of the results (some trials provided evidence for ⬎
`one recommendation) and comprise the evidentiary basis of the guideline
`recommendations, in addition to the trials in the CCO systematic review. The
`identified trials spanned from 2009 to 2012. The Data Supplement provides
`additional details of the results of the systematic review.
`To address the question of the role of hormonal/endocrine therapy, the
`systematic review identified three hormonal therapy plus HER2-targeted ther-
`apy studies, all in the first-line setting.7-9 Two studies addressed questions of
`how prior adjuvant HER2-targeted therapy may influence subsequent treat-
`
`ment choices.10,11 There was insufficient evidence to make evidence-based
`recommendations on some of these questions. Therefore, some recommen-
`dations were made on the basis of informal consensus and are labeled as such.
`
`Study Quality
`As seen in the quality assessment table (Table 1), study quality was
`formally assessed for the 11 studies identified. Design aspects related to indi-
`vidual study quality were assessed by one reviewer, with factors such as blind-
`ing, allocation concealment, placebo control, intention to treat, funding
`sources, and so on generally indicating an intermediate to high potential risk of
`bias for most of the identified evidence. The Methodology Supplement pro-
`vides definitions of ratings for overall potential risk of bias.
`
`RESULTS
`
`More extensive discussion and analysis of the literature review are
`provided in Data Supplement 6.
`
`CLINICAL QUESTION 1
`What is the optimal treatment for patients with HER2-positive
`advanced breast cancer?
`For patients with HER2-positive advanced breast cancer:
`
`Clinical Question 1.A
`Is HER2-targeted therapy recommended for all patients in the
`first-line setting?
`Recommendation 1.A.I. Clinicians should recommend HER2-
`targeted therapy–based combinations for first-line treatment, except
`for highly selected patients with ER-positive or PgR-positive and
`HER2-positive disease, for whom clinicians may use endocrine ther-
`apy alone (see Clinical Question 2). Type: evidence based. Evidence
`quality: high. Strength of recommendation: strong.
`Literature review and analysis. This recommendation is based
`on a body of evidence regarding first-line therapy, found both in the
`ASCO and CCO systematic reviews.4 CCO included the pivotal trial
`by Slamon et al21 and nine other RCTs of trastuzumab. These trials
`found a benefit for HER2-targeted therapy combinations, specifically
`with trastuzumab. The study by Slamon et al was the only first-line
`phase III trial that compared an HER2-targeted therapy plus chemo-
`therapy with chemotherapy alone. That trial found survival, time to
`progression (TTP), and overall response rate benefits in the trastu-
`zumab arm (see CCO evidence table at https://www.cancercare.on
`.ca/common/pages/UserFile.aspx?fileId⫽13,890). The CCO review
`found two phase III trials that compared HER2-targeted therapy plus
`endocrine therapy with endocrine therapy alone.7,8 Both of those trials
`found progression-free survival (PFS) and TTP benefits, but no over-
`all survival (OS) benefit, in the combination arm and will be discussed
`in the section on endocrine therapy (Clinical Question 2), along with
`another more recent trial.9 A separate ASCO guideline addresses the
`definition of and testing for HER2 positivity in patients with breast
`cancer and its role in treatment selection for these patients.6
`The ASCO systematic review results included five other
`first-line studies of various trastuzumab plus chemotherapy
`combinations.7,8,13-15 The ASCO systematic review also included
`studies in which patients in the interventional arms received lapa-
`tinib, pertuzumab, and/or trastuzumab emtansine (T-DM1).9-12,16
`Selected results of these trials are listed in Tables 2, 3, and 4; results
`from the trials on recommended agents are discussed here and in
`the Data Supplement.
`
`www.jco.org
`
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
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`High
`
`High
`
`?
`
`Intermediate
`
`Intermediate
`
`Intermediate
`High
`
`High
`
`High
`
`Intermediate
`
`Intermediate
`
`OverallRisk
`
`ofBias
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`Insignificant
`
`COIs
`
`⫹i
`
`—g
`
`⫹
`
`⫹
`
`⫹e
`
`⫹d
`⫹c
`
`⫹b
`
`?a
`
`⫹
`
`⫹
`
`ITT
`
`?
`
`⫹
`
`⫹
`
`—
`
`Partially
`
`Partially
`
`Partially
`
`Partially
`
`⫹
`
`?
`
`Partially
`
`?
`
`Partially
`
`—
`
`⫹
`
`?
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`Follow-Up
`Adequate
`
`ReliableMeasures
`
`Validatedand
`
`—
`
`?
`
`—
`
`⫹
`
`?
`
`—
`
`—
`
`?
`
`Partially
`
`Blinded
`
`iForefficacyanalysis.Safetyanalysisincludedrandomlyassignedpatientswhoreceivedⱖonedose.
`hDidnotmeettargetforOS.
`gForsafety.ModifiedITTanalysisincludedthosepatientsinsafetygroup,excludingonewhodidnotmeeteligibility.
`fMettargetaccrual,butthiswas⬍100perarm.
`eTimetoprogression,responserate,responseduration,andOS.
`dForefficacy.Safetyanalysisincludedallparticipantswhoreceivedⱖonedose.
`cOverallpopulationincludedpatientswithHER2-negativedisease.
`bForallpatientswhoreceivedⱖonedoseofassignedstudydrug.
`aIfpatientwithdrewfromstudyorwaslosttofollow-upwithoutrecordedtumorprogression,theirobservationwascensoredatdateoflastadequatetumorassessment.
`Abbreviations:COI,conflictofinterest;HER2,humanepidermalgrowthfactorreceptor2;ITT,intenttotreat;OS,overallsurvival.
`NOTE.⫹indicatescriterionwasmet;—indicatescriterionwasnotmet;?indicatesinsufficientdetail,notreported,and/oruncertainriskofbias.
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`Partially
`
`⫹
`
`Partially
`
`?
`
`⫹
`
`?
`
`—h
`
`?
`
`Partiallyf
`
`⫹
`
`⫹
`
`—
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`⫹
`
`?
`
`?
`
`?
`
`?
`
`⫹
`
`⫹
`
`⫹
`
`?
`
`⫹
`
`?
`
`⫹
`
`⫹
`
`?
`
`⫹
`
`?
`
`⫹
`
`⫹
`
`⫹
`
`?
`
`⫹
`
`?
`
`2012)
`(EGF104900;2010,
`
`Blackwelletal19,20
`
`(EGF100151;2010)
`Geyeretal18
`Cameronetal,17
`
`Gelmonetal16(MA.31/
`
`2012)
`GSKEGF108919;
`
`(JO17360;2010)
`
`Inoueetal15
`
`(BCIRG007;2011)
`
`Valeroetal14
`
`Anderssonetal13
`Schwartzbergetal9(2010)
`
`(HERNATA;2011)
`
`(TAnDEM;2009)
`
`Kaufmanetal8
`
`(eLEcTRA;2012)
`
`Huoberetal7
`
`etal12(EMILIA;2012)
`
`Blackwelletal,11Verma
`(CLEOPATRA;2012)
`
`Baselgaetal10
`
`Comparable
`
`Groups
`
`Sample
`Sufficient
`
`Size
`
`Allocation
`Concealed
`
`Randomization
`
`Adequate
`
`Study
`
`Table1.QualityAssessment
`
`2082
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`IMMUNOGEN 2224, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`(continuedonfollowingpage)
`
`HER2-Targeted Therapy Regimens for Patients With Advanced Breast Cancer
`
`16.5
`12.2
`
`11.4
`
`MediandurationofORR(months):
`
`45.9to57.7
`59.3to70.2
`
`51.8%
`
`64.7%
`
`2-yearsurvival:
`⬍.001
`
`6.5months
`
`Mediandurationof
`
`12.6months
`reviewed):
`(investigator
`response
`
`0.54to0.78
`
`HR,0.65
`
`12.4
`
`18.5
`
`0.64to9.70
`
`ORR:OR,2.49j,k
`
`4of35ORR,11(HER2positive
`4of31ORR,13
`
`alone)
`vnegative,letrozole
`
`7of26ORR,27
`
`⬍.001
`
`26.3to35.7
`38.6to48.6
`
`⬍.001h
`
`74.6to82.3
`82.0to88.5
`
`30.8
`
`43.6
`
`120of389
`
`173of397
`
`78.4
`
`85.2
`
`.001e
`
`4.2to17.5
`
`Difference,10.8c
`
`69.3
`
`80.2
`
`⬍.001
`
`0.55to0.85
`
`0.68g
`
`25.1monthsf
`
`.005d
`
`0.47to0.88
`
`23.6
`
`17.2
`
`96(deaths)
`
`69
`
`Investigator-assessedPFS:
`
`OtherEfficacyResults
`
`%
`
`No.
`
`1-YearSurvival(%)
`
`%
`
`No.
`
`RR
`
`OS(median)/Mortality
`
`Table2.EfficacyOutcomes
`
`.23
`
`0.35to1.29
`
`HR,0.67j
`
`NS
`
`15.2
`3.3
`
`14.1
`
`30.9monthsf
`
`HR,0.64
`
`35
`31
`
`26
`
`⬍.001
`
`0.55to0.77
`0.650
`
`StratifiedHR,
`
`496Median,6.4(304
`
`events)
`
`495Median,9.6(265
`
`events)
`
`⬍.001
`
`HRforprogression
`
`0.51to0.75
`ordeath,0.62
`
`12.4a,b
`
`18.5a,b
`
`406
`
`402
`
`P
`
`95%CI
`Summarystatistic
`
`Letrozolealone(HER2
`Letrozole
`
`receptorpositive)i
`negative,hormone
`
`Trastuzumabplus
`
`letrozole
`
`Huoberetal7(eLEcTRA;
`
`2012)
`
`P
`
`95%CI
`
`Summarystatistic
`
`capecitabine
`Lapatinibplus
`
`T-DM1
`
`etal12(EMILIA;2012)
`
`Blackwelletal,11Verma
`
`P
`
`95%CI
`
`Summarystatistic
`
`Trastuzumab,docetaxel,
`
`andplacebo
`
`docetaxel
`trastuzumab,and
`
`Pertuzumab,
`
`(CLEOPATRA;2012)
`
`Baselgaetal10
`
`TTP(months)
`
`PFS(months)
`
`Sample
`
`Size
`
`Study
`
`www.jco.org
`
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`2083
`
`IMMUNOGEN 2224, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`332days
`
`114days
`
`MedianTTF:
`
`10.74months
`
`9.43months
`
`Mediandurationofresponse:
`
`Giordano et al
`
`.003
`
`0.2to0.9
`OR,0.4
`
`CBR:
`
`.007
`
`2.1to6.3
`3.8to8.3
`
`.006
`
`2.0to6.3
`3.8to8.3
`
`HR,0.62
`
`HR,0.62
`
`3.9months
`
`3.8months
`
`TTP(populationcentrally
`
`5.6months
`positive):
`hormonereceptor
`confirmedas
`
`5.6months
`
`PFS:
`
`53.7to80.1)
`
`36of5367.9(95%CI,
`
`6.6to27.1)
`8of5414.8(95%CI,
`
`(continuedonfollowingpage)
`
`11.3
`
`24.1
`
`6
`
`13
`
`.97
`
`72
`
`72
`
`1.00
`
`59.3
`
`59.3
`
`6.8
`
`20.3
`
`82to93
`81to92
`
`118of141
`
`123of143
`
`88
`
`88
`
`.021
`
`0.2to0.9
`OR,0.4
`15
`28
`
`.18(PR)
`
`.99
`
`0.759to1.358
`
`HR,1.015
`
`37.1months(95%CI,
`
`32.6to43.6)
`
`37.4months(95%CI,
`
`30.7to43.1)
`
`.98
`
`0.71to1.42
`
`HR,1.01
`
`38.8months
`
`35.7months
`
`NS
`
`32.3months
`33.3months
`
`.325
`
`23.9months
`
`28.5months
`
`OtherEfficacyResults
`
`%
`
`No.
`
`1-YearSurvival(%)
`
`%
`
`No.
`
`RR
`
`OS(median)/Mortality
`
`Table2.EfficacyOutcomes(continued)
`
`.57
`
`0.694to1.203
`HR,0.914
`
`9.30to13.47)
`
`11.07(95%CI,
`
`9.36to12.12)
`
`10.35(95%CI,
`
`.67
`
`0.71to1.25
`
`HR,0.94
`
`15.3
`
`12.4
`
`⬍.001(log
`
`rank)
`
`.0016
`
`0.47to0.84
`
`2.4(95%CI,2
`
`HR,0.63
`to4.6)
`
`4.8(95%CI,3.7
`
`to7)
`
`14.6
`
`3.7
`
`.019
`
`0.53to0.96
`
`HR,0.71
`
`3
`
`8.2
`
`53
`
`55
`
`132
`
`131
`
`141
`
`143
`
`108
`111
`
`104
`
`103
`
`TTP(months)
`
`PFS(months)
`
`Sample
`
`Size
`
`Trastuzumabplus
`
`docetaxel
`
`docetaxel
`bytrastuzumabplus
`Trastuzumabfollowed
`
`(JO17360;2010)
`
`Inoueetal15
`
`P
`
`95%CI
`Summarystatistic
`
`trastuzumab
`Docetaxeland
`
`Docetaxel,carboplatin,
`
`andtrastuzumab
`
`Valeroetal14(BCIRG007;
`
`2011)
`
`P
`
`95%CI
`Summarystatistic
`
`Trastuzumabplus
`
`vinorelbine
`
`Trastuzumabplus
`
`docetaxel
`
`(HERNATA;2011)
`
`Anderssonetal13
`
`P
`
`95%CI
`Summarystatistic
`Placeboplusletrozole
`Lapatinibplusletrozole
`
`Schwartzbergetal9(2010)
`
`P
`
`95%CI
`Summarystatistic
`
`Anastrozole
`
`Trastuzumabplus
`
`anastrozole
`
`(TAnDEM;2009)
`
`Kaufmanetal8
`
`Study
`
`2084
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2014 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 28, 2014. For personal use only. No other uses without permission.
`Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
`
`IMMUNOGEN 2224, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`HER2-Targeted Therapy Regimens for Patients With Advanced Breast Cancer
`
`.027
`
`0.52to0.98
`
`28b
`
`13
`
`HR,0.71
`
`.46
`
`0.6to3.9
`
`10.3(95%CI,3.4to
`
`OR,1.5
`12.3)
`
`6.9(95%CI,5.9to
`
`16.4)
`
`PFSat6months(%):
`
`⬍.001
`
`0.43to0.77
`
`HR,0.57
`
`18.6weeks(4.3months)
`
`27.1weeks(6.2months)
`
`TTP:
`
`.003
`
`1.15to1.92
`
`HR,1.48
`
`13.7months
`
`9months
`
`CentrallyconfirmedHER2plusPFS:
`
`⬍.01
`
`1.77to4.47
`
`HR,2.81
`
`.008
`
`1.2to3.30
`OR,2.0
`
`13.9(95%CI,9.5to
`
`19.5)
`
`23.7(95%CI,18to
`
`30.3)
`
`.106
`
`0.53to1.07
`
`51.6weeks19
`
`39.0weeks
`
`.206
`
`0.70to1.08
`
`HR,0.8717
`
`64.7weeksl
`
`75weeksl
`
`NS
`
`HR,1.1
`
`NR
`
`.04
`
`1.03to7.18
`
`OtherEfficacyResults
`
`%
`
`No.
`
`1-YearSurvival(%)
`
`%
`
`No.
`
`RR
`
`OS(median)/Mortality
`
`Table2.EfficacyOutcomes(continued)
`
`lIntentiontotreat.
`kForarmonevthree:OR,5.34;95%CI,1.83to15.58;P⫽.0024.
`jComparingtwoHER2-positivearms.
`iPerGermansitesamendment;HER2-negative,hormonereceptor–positivegroupreceivedletrozolealone.
`hP⬍.001inVermaetal.12
`gHRfordeathresultingfromanycause.
`fEfficacystoppingboundary:HR,0.73orP⫽.0037.
`eOSdidnotcrossstoppingboundary;therefore,ORRwasexploratory.
`dInterimanalysisdidnotmeetstoppingboundaryattimeofpublication.
`cORR.
`bByindependentreview.
`aMedianPFSperprespecifiedsubgroupof88of808patientswhoreceivedadjuvantorneoadjuvantchemotherapywithtrastuzumab.
`survival;PFS,progression-freesurvival;RR,responserate;T-DM1,trastuzumabemtansine;TTF,timetotreatmentfailure;TTP,timetoprogression.
`Abbreviations:CBR,clinicalbenefitrate;HER2,humanepidermalgrowthfactorreceptor2;HR,hazardratio;NR,notreached;NS,notsignificant;OR,objectiveresponse;ORR,objectiveresponserate;OS,overall
`
`HR,0.75
`
`.008
`
`0.57to0